Contact lens material

ABSTRACT

Cross-linked copolymers which are obtainable by polymerising a neutral diluent monomer or monomers, a monomer or monomers bearing a center of permanent positive charge, and a bifunctional and/or trifunctional cross-linking agent, are suitable for use in contact lenses. Process for producing them by copolymerization, contact lens material comprising them, contact lenses made of them and processes for producing contact lenses from them.

This is a divisional of application Ser. No. 08/050,032 filed Apr. 28,1992 now U.S. Pat. No. 6,420453.

The present invention relates to copolymers, in particular suitable foruse in contact lenses.

The use of synthetic hydrogels for contact lenses was first demonstratedby Wichtecte and Lim in the 1960's. Early hydrogels employed2-hydroxyethyl methacrylate (HEMA) as principal monomer, together withsome of the homologous esters of the glycol monomethacrylate series suchas diethylene glycol monomethacrylate and tetraethylene glycolmonomethacrylate. It was later found that slightly cross-linkedcopolymers of the higher glycol monomethyacrylates and 2-hydroxyethylmethacrylate yielded transparent hydrogels that swelled in water to ahigher hydration than the hydrogels of 2-hydroxyethyl methacrylate.

The water content of hydroxyalkyl methacrylate based gels can be furtherincreased by the addition of vinyl lactams, methacrylic acids, acrylicacids, acrylamides and methacrylamides. Although the required degree ofgel hydration can be achieved by the addition of anionic monomers, it iswell known that these gels display high levels of protein deposition onand occasionally within the gel matrix.

It has now surprisingly been found that effective contact lens materialswhich have both good transparency and a high degree of waterswellability are provided by copolymers which have a permanent positivecharge built into them. Such polymers are formed by polymerising andcrosslinking a neutral diluent monomer, for example HEMA, with aco-monomer bearing a centre of permanent positive charge. Theseformulations have been found to have a high level of protein resistanceto tear component deposition and a reduction in lens water loss.

Accordingly, the present invention provides a crosslinked copolymerwhich is obtainable by polymerising a neutral diluent monomer ormonomers, a monomer or monomers bearing a centre of permanent positivecharge, and a bifunctional or trifunctional crosslinking agent.

The crosslinked copolymers of the present invention therefore compriseresidues of a diluent monomer or monomers, a monomer or monomers bearinga centre of permanent positive charge, and a bifunctional ortrifunctional crosslinking agent.

The copolymers of the invention may be xerogels which do not contain anywater. Alternatively, they may be in the form of hydrogels which docontain water.

The invention also provides a process for producing such a crosslinkedcopolymer, a contact lens material comprising such a copolymer, acontact lens made from such a copolymer, and use of such a copolymer orcontact lens material in the production of a contact lens.

Diluent Comonomer

The diluent monomer can act as a solvent for the comonomers duringcopolymerisation to produce the copolymer if no additional solvent ispresent. Where the diluent monomer and monomer bearing the centre ofpermanent positive charges are immiscible a solvent can be used to aidmixing.

Particular examples of diluent comonomers include alkyl (alk)acrylatepreferably containing 1 to 12, more preferably 1 to 4, carbon atoms inthe alkyl group of the ester moiety, such as a methyl (alk)acrylate andbutyl (alk)acrylate; a dialkylamino alkyl (alk)acrylate, preferablycontaining 1 to 4 carbon atoms in each alkyl moiety of the amine and 1to 4 carbon atoms in the alkylene chain, e.g. 2(dimethylamino)ethyl(alk)acrylate; an alkyl (alk)acrylamide preferably containing 1 to 4carbon atoms in the alkyl group of the amide moiety; a hydroxyalkyl(alk)acrylate preferably containing from 1 to 4 carbon atoms in thehydroxy moiety, e.g. a 2-hydroxyethyl (alk)acrylate; or a vinyl monomersuch as an N-vinyl lactam, preferably containing from 5 to 7 atoms inthe lactam ring for instance vinyl pyrrolidone; styrene or a styrenederivative which for example is substituted on the phenyl ring by one ormore alkyl groups containing from 1 to 4 carbon atoms, and/or by one ormore halogen, such as fluorine atoms.

It is to be understood that throughout the specification (alk)acrylate,(alk)acrylic and (alk)acrylamide mean acrylate or alkacrylate, acrylicor alkacrylic and acrylamide or alkacrylamide respectively. Preferablyalkacrylate, alkacrylic and alkacrylamide groups contain from 1 to 4carbon atoms in the alkyl group thereof and are most preferablymethacrylate, methacrylic or methacrylamide groups. Similarly(meth)acrylate, (meth)acrylic and (meth)acrylamide shall be understoodto mean acrylate or methacrylate, acrylic or methacrylic and acrylamideor methacrylamide respectively.

Preferably the diluent monomer is selected from vinylpyrrolidone,2-hydroxyethyl methacrylate, methyl methacrylate and mixtures thereof,most preferably 2-hydroxyethyl methacrylate, methyl methacrylate andmixtures thereof. In one embodiment diluent monomers arevinylpyrrolidone, 2-hydroxyethyl methacrylate and mixtures thereof.

Comonomers Bearing A Centre of Permanent Positive Charge

The comonomer bearing the centre of permanent positive charge can eitherbe cationic or zwitterionic. In the latter case the monomer includeswithin its structure not only a centre of permanent positive charge butalso a centre of negative charge. Typically the centre of permanentpositive charge in both cationic and zwitterionic comonomers is providedby a quaternary nitrogen atom.

Preferred comonomers which bear a centre of positive charge are ofgeneral formula (I)

Y—B—X  (I)

wherein

B is a straight or branched alkylene, oxaalkylene or oligo-oxaalkylenechain or if X contains a carbon-carbon chain between B and the centre ofpermanent positive charge or if Y contains a terminal carbon atom, avalence bond,

X is a group bearing a centre of permanent positive charge and

Y is an ethylenically unsaturated polymerisable group selected from

wherein:

R is hydrogen or a C₁-C₄ alkyl group;

A is —O— or —NR¹— where R¹ is hydrogen or a C₁-C₄ alkyl group or R¹ is—B—X where B and X are as defined above.

K is a group —(CH₂)_(p)CO(O)—, —(CH₂)_(p)C(O)O—, —(CH₂)_(p)OC(O)O—,—(CH₂)_(p)NR²—, —(CH₂)_(p)NR²C(O)—, —(CH₂)_(p)C(O)NR²—,(CH₂)_(p)NR²C(O)O—, —(CH₂)_(p)OC(O)NR²—, —(CH₂)_(p)NR²C(O)NR²— (in whichthe groups R² are the same or different), —(CH₂)_(p)O—, —(CH₂)_(p)SO₃—,or, optionally in a combination with B, a valence bond, and p is from 1to 12 and R² is hydrogen or a C₁-C₄ alkyl groups

The proviso on whether B may be a valence bond ensures that the centreof permanent positive charge in X is not directly bonded to aheteroatom, such as an oxygen or nitrogen atom in Y.

Preferred monomers which bear a centre of positive charge are those ofgeneral formula (II) or (III).

where R, A, B and X are as defined with reference to formula (I).

Preferably R is hydrogen, methyl, or ethyl , more preferably methyl, sothat the monomer of formula (II) is an acrylic acid, methacrylic acid orethacrylic acid derivative.

In the compounds of formula (III) K may be a valence bond and B a group,K may be a group and B a valence bond, both K and B may be groups or Kand B may together be a valence bond. Preferably B is a group where K isa valence bond. Where K is a group then preferably p is from 1 to 6,more preferably 1, 2 or 3 and most preferably p is 1. When K is a group—(CH₂)_(p)NR²—, —(CH₂)_(p)NR²C(O)—, —(CH₂)_(p)C(O)NR²—,—(CH₂)_(p)NR²C(O)O—, —(CH₂)_(p)OCNR²— or —(CH₂)_(p)NR²C(O)NR²— then R²is preferably hydrogen, methyl or ethyl, more preferably hydrogen.

Preferably B is:

an alkylene group of formula —(CR³ ₂)_(a)—, wherein the groups —(CR³ ₂)—are the same or different, and in each group —(CR³ ₂)— the groups R³ arethe same or different and each group R³ is hydrogen or C₁₋₄ alkyl,preferably hydrogen, and a is from 1 to 12, preferably 1 to 6;

an oxaalkylene group such as alkoxyalkyl having 1 to 6 carbon atoms ineach alkyl moiety, more preferably —CH₂O(CH₂)₄—;

an oligo-oxaalkylene group of formula —[(CR⁴ ₂)_(b)O]_(c)(CR⁴ ₂)_(b)—where the groups —(CR⁴ ₂)— are the same or different and in each group—(CR⁴ ₂)— the groups R⁴ are the same or different and each group R⁴ ishydrogen or C₁₋₄ alkyl, preferably hydrogen, and b is 2 or 3 and c isfrom 2 to 11, preferably 2 to 5;

or a valence bond but only if X contains a carbon-carbon chain between Band the centre of positive charge, or if Y contains a terminal carbonatom.

Preferred groups B include a valence bond and alkylene, oxaalkylene andoligo-oxaalkylene groups of up to 12 carbon atoms.

Preferred groups X are the groups of formula (IVA), (IVB), (IVC), (IVD),(IVE) and (IVF) as defined below, of which the groups of formula (IVC)are particularly preferred.

The groups of formula (IVA) are:

—N^(⊕)(R⁵)₃Z^(⊖)  (IVA)

where the groups R⁵ are the same or different and each is hydrogen orC₁₋₄ alkyl and Z^(⊖) is a counterion.

Preferably the groups R⁵ are all the same. It is also preferable that atleast one of the groups R⁵ is methyl, and more preferable that all thegroups R⁵ are methyl.

The counterion Z^(⊖) present in the compounds of formula (II) or (III)containing a group of formula (IVA) is such that the compounds areneutral salts. The counterion may be exchanged with ions inphysiological fluids and thus the specific nature of the counterion isnot critical in the present invention. However, physiologicallyacceptable counterions are preferred. Suitable physiologicallyacceptable counterions include halide anions, such as chloride, bromideor fluoride ions, other inorganic anions such as sulphate, phosphate andphosphite and organic anions such as aliphatic mono-, di- ortri-carboxylate anions containing from 2 to 25 carbon atoms andoptionally bearing one or more hydroxyl groups e.g. acetate, citrate andlactate.

When X is a group of formula (IVA), preferably B is a group of formula—(CR³ ₂)— or —(CR³ ₂)₂—, eg. —(CH₂)— or —(CH₂CH₂)—.

The groups of formula (IVB) are:

where the groups R⁶ are the same or different and each is hydrogen orC₁₋₄ alkyl and d is from 2 to 4.

Preferably the groups R⁶ are the same. It is also preferable that atleast one of the groups R⁶ is methyl, and more preferable that thegroups R⁶ are both methyl.

Preferably d is 2 or 3, more preferably 3.

When X is a group of formula (IVB) preferably B is a group of formula—(CR³ ₂)— or —(CR³ ₂)₂—, eg. —(CH₂)— or —(CH₂CH₂)—.

The groups of formula (OVA) are:

where the groups R⁷ are the same or different and each is hydrogen orC₁₋₄ alkyl, and e is from 1 to 4.

Preferably the groups R⁷ are the same. It is also preferable that atleast one of the groups R⁷ is methyl, and more preferable that thegroups R⁷ are all methyl.

Preferably e is 2 or 3, more preferably 2.

When X is a group of formula (IVC) preferably B is a group of formula—(CR³ ₂)— or —(CR³ ₂)₂—, eg. —(CH₂)— or —(CH₂CH₂)—.

The groups of formula (IVD) are:

wherein the groups R⁸ are the same or different and each is hydrogen orC₁₋₄ alkyl, B¹ is a valence bond or straight or branched alkylene,oxaalkylene or oligo-oxaalkalkylene group, f is from 1 to 4 and if B isother than a valence bond, Z is 1 and if B is a valence bond Z is 0 if Xis directly bonded to an oxygen or nitrogen atom, and otherwise Z is 1.

Preferably the groups R⁸ are the same. It is also preferable that atleast one of the groups R⁸ is methyl, and more preferable that thegroups R⁸ are all methyl.

Preferably f is 1 or 2, more preferably 2.

Preferably B¹ is:

a valence bond;

an alkylene group of formula —(CR^(3a) ₂)_(aa)—, wherein the groups—(CR^(3a) ₂)— are the same or different, and in each group —(CR^(3a) ₂)—the groups R^(3a) are the same or different and each group R^(3a) ishydrogen or C₁₋₄ alkyl, preferably hydrogen, and aa is from 1 to 24,preferably 6 to 18;

an oxaalkylene group such as alkoxyalkyl having 1 to 6 carbon atoms ineach alkyl moiety, more preferably —CH₂O(CH₂)₄—; or

an oligo-oxaalkylene group of formula —[(CR^(4a) ₂)_(ba)O]_(ca)— wherethe groups —(CR^(4a) ₂)— are the same or different and in each group—(CR^(4a) ₂)— the groups R^(4a) are the same or different and each groupR^(4a) is hydrogen or C₁₋₄ alkyl, preferably hydrogen, and ba is 2 or 3and ca is from 1 to 12, preferably 1 to 6.

Preferred groups B¹ include a valence bond and alkylene, oxaalkylene andoligo-oxaalkylene groups of up to 24 carbon atoms.

In one embodiment B and B¹ are the same.

The groups of formula (IVE) are:

wherein the groups R⁹ are the same or different and each is hydrogen orC₁-C₄ alkyl, B² is a valence bond or a straight or branched alkylene,oxaalkylene or oligo-oxaalkylene group, g is from 1 to 4 and if B isother than a valence bond, Z is 1 and if B is a valence bond Z is 0 if Xis directly bonded to an oxygen or nitrogen atom and otherwise Z is 1.

Preferably the groups R⁹ are the same. It is also preferable that atleast one of the groups R⁸ is methyl, and more preferable that thegroups R⁸ are all methyl.

Preferably g is 1 or 2, more preferably 2.

Preferably B² is:

a valence bond;

an alkylene group of formula —(CR^(3b) ₂)_(ab)—, wherein the groups—(CR^(3b) ₂)— are the same or different, and in each group —(CR^(3b)₂)—the groups R^(3b) are the same of different and each group R^(3b) ishydrogen or C₁₋₄ alkyl, preferably hydrogen, and ab is from 1 to 24,preferably 6 to 18,

an oxaalkylene group such as alkoxyalkyl having 1 to 6, carbon atoms ineach alkyl moiety, more preferably —CH₂O(CH₂)₄—; or

an oligo-oxaalkylene group of formula —[(CR^(4b) ₂)_(bb)O]_(cb)— wherethe groups —(CR^(4b) ₂)— are the same or different and in each group—(CR^(4b) ₂)— the groups R^(4b) are the same or different and each groupR^(4b) is hydrogen or C₁₋₄ alkyl, preferably hydrogen, and bb is 2 to 6and cb is from 1 to 12, preferably 1 to 6.

Preferred groups B² include a valence bond and alkylene, oxaalkylene andoligo-oxaalkylene groups of up to 24 carbon atoms.

In one embodiment B and B² are the same.

The groups of formula (IVF) are:

wherein the groups R¹⁰ are the same or different and each is hydrogen orC₁₋₄ alkyl, B³ is a valence bond or a straight or branched alkylene,oxaalkylene or oligo-oxaalkylene group, h is from 1 to 4 if B is otherthan a valence bond, Z is 1 and if B is a valence bond Z is 0 if X isdirectly bonded to an oxygen or nitrogen atom and otherwise Z is 1.

Preferably the groups R¹⁰ are the same. It is also preferable that atleast one of the groups R¹⁰ is methyl, and more preferable that thegroups R¹⁰ are all methyl.

Preferably h is 1 or 2, more preferably 2.

Preferably B³ is:

a valence bond;

an alkylene group of formula —(CR^(3c) ₂)_(ac)—, wherein the groups—(CR^(3c) ₂)— are the same or different, and in each group —(CR^(3c) ₂)—the groups R^(3c) are the same or different and each group R^(3c) ishydrogen or C₁₋₄ alkyl, preferably hydrogen, and ac is from 1 to 24,preferably 6 to 18;

an oxaalkylene group such as alkoxyalkyl having 1 to 6 carbon atoms ineach alkyl moiety, more preferably —CH₂O(CH₂)₄—; or

an oligo-oxaalkylene group of formula —[(CR^(4c) ₂)_(bc)O]_(cc)— wherethe groups —(CR^(4c) ₂)— are the same or different and in each group—(CR^(4c) ₂)— the groups R^(4c) are the same or different and each groupR^(4c) is hydrogen or C₁₋₄ alkyl, preferably hydrogen, and be in 2 to 6and cc is from 1 to 12, preferably 1 to 6.

Preferred groups B³ include a valence bond and alkylene, oxaalkylene andoligo-oxaalkylene groups of up to 24 carbon atoms.

In one embodiment B and B³ are the same.

According to one particular embodiment, the monomer bearing a centre ofpermanent positive charge is a monomer of formula (V)

wherein BB is a straight or branched C₁-C₆ alkylene chain optionallyinterrupted by one or more oxygen atoms;

nn is from 1 to 12

R¹¹ is H or a C₁-C₄ alkyl group; and

YY is a group which includes a centre of positive charge. Morepreferably,

YY is a group selected from:

—^(⊕)N(CH₃)₃;  (VIA)

the group BB in (VID) and (VIE) being a linear or branched alkylenechain as defined above and nn being as defined above.

Preferably BB is a group selected from —CH₂—, —C(R¹²)₂—, in which R¹² isC₁₋₄ alkyl, and —CH₂—CH₂—O—.

Preferably in compounds of formula (V), R¹¹ is hydrogen or methyl.

When X is a group as defined under (VID) or (VIE), the group (BB)_(nn)is preferably chosen to avoid steric hindrance in the vicinity of theadjacent —OC(O)— group, the reactivity of which could be adverselyaffected by such steric hindrance.

Preferred examples of co-monomers of formula (I) are:

Particular examples of preferred comonomers bearing a centre ofpermanent positive charge are 2(methacryloyloxy)ethyl-2′(trimethylammonium)ethyl phosphate inner salt[Compound C above] and1[4(4′-vinylbenzyloxy)butane]-2″(trimethylammonium)ethyl phosphate innersalt [a compound of formula (III)].

Comonomers bearing a centre of permanent positive charge, such as thoseof formulae (II) and (III), and comonomers of formula (V) may beprepared by conventional techniques using known reactions, for exampleusing a suitable substituted alkyl (alk)acrylate, glycerophosphorylcholine or suitable substituted styrene as starting material.

Examples of suitable substituted alkyl (alk)acrylates includedimethylaminoethyl(meth)acrylate and 2-hydroxyethyl(meth)acrylate.

Comonomers of formula (II) or (III) containing a group of formula (IVA),(IVB) or (IVC) and comonomers of formula (V) including a group offormula (VIA), (VIB), and (VIC) may be prepared as described inReference Examples 1 to 4 or by analogous known methods.

Comonomers of formula (II) or (III) containing a group of formula (IVD)and comonomer of formula (V) including a group of formula (VID) may beprepared by selective acylation of glycerophosphorylcholine or analoguesthereof at the primary hydroxyl group with an activated acid derivativesuch as an acid anhydride O[C(O)B¹CH₃]₂ or an acid halide CH₃B¹COHalwhere B¹ is as defined above and Hal is halogen, followed by acylationof the secondary hydroxyl group with an appropriate acylating agent, forexample methacryloyl chloride. Purification, for example by columnchromatography on a suitable support, may be performed after eachacylation or after the second acylation only. Suitable activated acidderivatives include acid anhydrides, acid halides, reactive esters andimidazolides. The acylations may be performed in a suitable anhydrous,aprotic solvent, for example N,N-dimethylformamide, optionally in thepresence of a suitable non-nucleophilic base, for example triethylamine.

Alternatively, the primary alcohol group in glycerophosphoryl choline oran analogue thereof may be blocked by reaction with a suitableprotecting group reagent, for example t-butyldimethylsilyl chloride,under standard conditions and the secondary hydroxy group then treatedwith at acylating agent such as methacryloyl chloride. Thet-butyldimethylsilyl protecting group may be removed by treatment with adilute organic or mineral acid, for example p-toluene sulphonic acid,hydrochloric acid or with tetra-butylammonium fluoride. The deblockedprimary hydroxyl group may then be treated with an activated acidderivative such as an acid anhydride O[C(O)B¹CH₃]₂ or acid halideCH₃B¹COHal where B¹ is as defined above, and Hal is halogen.

Analogues of glycerophosphorylcholine may be prepared by reaction ofphosphorus oxychloride with a bromoalcohol in an inert aprotic solvent,such as dichloromethane, to give a bromoalkylphosphorodichloridate. Thedichloro derivative thus produced may then be treated with 2,2-dimethyl1,3-dioxolane-4-methanol in the presence of a base, for exampletriethylamine, followed by acid hydrolysis to give abromoalkylphosphorogylcerol derivative. This may then be treated with anamine NR⁸ ₃, where R⁸ is as defined above, for example trimethylamine,to generate the glycerophosphorylcholine analogue. This preparation isdepicted in the following scheme.

where R⁸ and f are as defined in relation to groups of formula (IVD)

Comonomers of formula (II) or (III) containing a group of formula (IVE)and comomers of formula (V) containing a group of formula (VIE) may beprepared by the selective acylation of glycerophosphorylcholine or ananalogue thereof at the primary hydroxyl group with for example,methacryloyl chloride followed by reaction at the secondary hydroxylgroup using an activated acid derivative, such as an acid halideO[C(O)B²CH₃]₂ or an acid halide CH₃B²COHal, where B² is as defined aboveand Hal is halogen. The intermediates and final products may bepurified, as necessary using column chromatography. Optionally,protecting group strategy, similar to that outlined above in relation toproduction of comonomers containing a group of formula (IVD), may beemployed.

Comonomers of formula (II) or (III) containing a group of formula (IVF)may be prepared in an analogous manner to comonomers containing groupsof formula (IVD) or (IVE).

Crosslinking Comonomers

The copolymers of the invention also comprise residues of difunctionaland/or trifunctional comonomers. Such comonomers are capable ofcrosslinking the polymer during polymerisation. Conventionalcrosslinking agents may be used.

Examples of suitable crosslinking comonomers include alkane diol ortriol di- or tri(alk)acrylates, eg (meth)acrylates, preferablycontaining 1 to 8 carbon atoms in the diol or triol residue; alkylenedi- or tri(alk)acrylamides, e.g. (meth)acrylamides, preferablycontaining 1 to 6 carbon atoms in the alkylene group and and di- ortri-vinyl compounds such as di- or tri-vinyl benzene compounds.Particular examples of crosslinking agents includeethyleneglycoldimethacrylate, tetraethyleneglycol dimethacrylate,trimethylolpropanetrimethacrylate and N,N-methylenebisacrylamide.

Optionally the comonomer mixture used for polymerising the copolymerfurther comprises a gel swelling monomer such as an N-vinyl lactam,methacrylic acid or acrylic acid and where appropriate a bulking orsolvating agent such as a solvent, for example, an alcohol or water.

Polymers of the invention may be prepared by copolymerising monomersbearing a centre of permanent positive change, diluent monomers andcrosslinking monomers usually by bulk polymerisation in an appropriatemould. Additionally a solvent or solvent mixture may be included toprovide a suitable reaction medium for immiscible comonomers. Suitablesolvents include water, halogenated organic solvents and non-halogenatedorganic solvents. Initiators and/or reagents to modify the bulkmorphology of the final polymer may also be included. Any conventionaltechnique may be used for the polymerisation, typically thermalpolymerisation or ultraviolet polymerisation.

The invention therefore further provides a method of preparing acrosslinked polymer which comprises copolymerising a monomercomposition, such as a monomer solution, comprising a diluent monomer ormonomers, a comonomer or comonomers including within its structure acentre of permanent positive charge, and a monomoner or monomers whichwill crosslink the resultant polymer. Optionally, the monomercomposition further comprises a solvent or solvent mixture and apolymerisation initiator or initiators.

The monomer composition which is subjected to polymerisation typicallycomprises at least 30%, preferably at least 60%, and up to 99.79% byweight of diluent monomer. It typically comprises at least 0.2% and upto 50% monomer or monomers which contain a centre of permanent positivecharge and from 0.01% to 20% by weight of crosslinking monomer.Optionally up to 10% by weight of gel swelling monomer is included.

In one embodiment the monomer composition which is subjected topolymerisation typically comprises at least 70%, preferably at least 80%by weight of the diluent monomer. It further comprises at least 0.2% andup to 20% of monomer or monomers which bear a centre of permanentpositive charge and, optionally, up to 10% by weight of gel-swellingmonomer or monomers.

The monomer composition may comprise conventional further polymeringredients such as cross-linking agents and polymerisation initiators.These further ingredients are in one embodiment used in a total amountfrom 0.1 to 5%, typically from 0.2 to 3% and preferably about 0.5% byweight relative to the weight of the monomer composition prior topolymerisation.

Preferably the monomer composition comprises at least 0.01% and up to10% of crosslinking monomer or monomers.

Examples of suitable initiators includebis(4-tertiarybutylcyclohexyl)-peroxydicarbonate, benzoylperoxide,2,2′-azo-bis(2-methylpropionitrile) [i.e. azo-bis-isobutyro nitrile],1-benzyl-2-hydroxy-2-dimethylethane-1-one and benzoin methylether. Aninitiator is generally used in a total amount from 0.1% to 5, typicallyfrom 0.2% to 3% and preferably about 0.5% by weight relative to theweight of the total monomer composition prior to polymerisation.

Additionally the monomer composition may have added to it a solvent orsolvent mixture. Example's of suitable solvents are ethanol, methanoland water. When present, solvent suitably comprises from 0.1 to 50weight % of the total reaction mixture, preferably from 5 to 40 weight%.

The polymer is prepared by dissolving the monomer or monomers bearingthe centre of positive charge in the diluent monomer or monomers ordiluent monomer/solvent mixture together with the crosslinking monomeror monomers and if present the polymerisation initiator or initiators.The solution thus formed is then purged with nitrogen, to remove anyoxygen which may be present before the polymerisation process is begun.Polymerisation is carried out in a sheet-forming mould, a contact lensprecursor button (thick round disc) mould, a contact lens mould or toprovide a cylindrical polymer rod. For example, when carried out in asheet-forming mould the monomer solution may be injected between twospaced plates and then polymerised in situ to generate a polymer sheet.

Generally the copolymers of the invention will be produced bycopolymerisation in the absence water. This produces a xerogel materialwhich can be moulded into contact lenses directly or moulded to givecontact lens buttons which can be lathe cut using methods known in theart to produce contact lenses. The xerogel material may be washed inwater or in aqueous buffer to remove any excess monomer and initiator.The xerogel material can be subsequently hydrated to produce hydrogelwith an equilibrium water content of up to 90%, and preferably from 30to 80%.

The polymers of the invention are both transparent and water swellableand therefore suitable for use as contact lens materials. In particular,the polymer may be suitable for use in contact lenses which are forexample soft or gas permeable contact lenses.

The invention further provides contact lenses made from polymers of theinvention as hereinbefore defined.

The invention may be further illustrated by the following examples.

EXAMPLE 1 Formation of2(methacryloyloxyethyl)-2′(trimethylammonium)ethyl phosphate InnerSalt-co-2-hydroxyethylmethacrylate-co-ethylenegdycoldimethacrylateButtons

2(methacryloyloxyethyl)-2′(trimethylammonium)ethyl phosphate inner salt(compound C) (4.86 g) was dissolved in 2-hydroxyethylmethacrylate (14.8g), together with ethyleneglycodimethacrylate (0.25 g) andbis(4-tertiarybutylcyclohexyl)-peroxydicarbonate (0.048 g). Thissolution was de-gassed with nitrogen gas and then pipetted into an openstainless steel contact lens button mould. The mould was placed in anoven in a nitrogen atmosphere at 50° C. for 1¼ hours. After this timethe mould was removed. The buttons were pushed out of the mould and thereaction completed by heating at 70° C. in a vacuum oven for 24 hours.The buttons were optically clear and could be machined to make contactlenses.

EXAMPLE 2 Formation of 2(methacroyloxyethyl)-2′(trimethylammonium)ethylphosphate InnerSalt-co-2-hydroxyethylmethacrylate-co-ethyleneglycoldimethacrylateButtons by photopolymerisation

2(methacryloyloxyethyl)-2′(trimethylammonium)ethyl phosphate inner salt(compound C) 5.00 g was dissolved in 2-hydroxyethylmethacrylate (14.2 g)together with ethyleneglycoldimethacrylate (0.2 g),1-benzyl-2-hydroxy-2-dimethylethane-1-one (0.2 g) andbis(4-tertiarybutylcyclohexyl)-peroxydicarbonate (0.02 g). The solutionwas de-gassed with N₂ and then pipetted into an open stainless steelcontact lens button mould. The monomer solutions were irradiated with a100 w/inch medium pressure, mercury vapour lamp for 2 minutes. Thereaction was completed thermally at 70° C. in a vacuum oven for 24hours. The resulting buttons were machined to make contact lenses.

EXAMPLE 3 Formation of2(methacryloyloxyethyl)-2′(trimethylammonium)ethyl phosphate InnerSalt-co-methylmethacrylate-co-ethyleneglycoldimethacrylate Buttons

2(methacryloyloxyethyl)-2′(trimethylammonium)ethyl phosphate inner salt(5.76 g) was dissolved in ethanol (6.5 ml) and methylmethacrylate (7.5g). Ethyleneglycoldimethyacrylate (0.21 g),1-benzyl-2-hydroxy-2-dimethylethane-1-one (0.2 g) andbis(4-tertiarybutylcyclohexyl)-peroxydicarbonate (0.01 g) were added tothe solution and dissolved. The resulting solution was degassed with thegas and poured into an open stainless steel contact lens button mould.The solutions were then irradiated by a 100 W/inch medium pressuremercury vapour lamp for 2 minutes. The reaction was completed thermallyat 70° C. in a vacuum oven for 24 hours. The ethanol was removed fromthese buttons by heating at 80° C. for 48 hours in a vacuum oven. Theresulting buttons were machined to make contact lenses.

EXAMPLE 4 Formation of2(methacryloyloxyethyl)-2′(trimethylammonium)ethyl phosphate InnerSalt-co-methylmethacrylate-co-ethyleneglycodimethylacrylate Rod

A xerogel rod (1 cm diameter×10 cm) was produced as follows:

2(methacryloyloxyethyl)-2′(trimethylammonium)ethyl phosphate inner salt(compound C) (5.77 g) was mixed with ethanol (6.5 g), methylmethacrylate(7.4 g), ethyleneglycoldimethacrylate (0.2 g) andbis(4-tertiarybutylcyclohexyl)-peroxydicarbonate (0.03 g). The mixturewas added to a polypropylene tube (1 cm diameter×10 cm) which was sealedat one end. N₂ gas was bubbled through the solution and then a capplaced over the end of the tube. The tube was then placed in an oven at50° C. for 1.5 hours. After this time the gelled rod of polymer wasremoved from the tube.

The reaction was completed at 70° C. for 24 hours. After this time therod was cut into 1 cm cylinders. These cylinders were heated in a vacuumoven at 80° C. for 48 hours in order to removed the ethanol. Theresulting buttons were machined into lenses.

EXAMPLE 5 Formation of2(methacryloyloxyethyl)-2′(trimethylammonium)ethyl phosphate InnerSalt-co-2-hydroxyethylmethacrylate-co-ethyleneglycoldimethylacrylateMembrane

2(methacryloxyethyl)-2(trimethylammonium)ethyl phosphate inner salt(compound C) (3.60 g) was dissolved in 2-hydroxyethylmethacrylate (6.27g) together with ethyleneglycoldimethacrylate (0.12 g) as a crosslinkingagent and azobisisobutyronitrile (0.2 g) as a polymerisation initiator.The resultant monomer solution was then deoxygenated by bubblingnitrogen through for 5 minutes.

The monomer solution thus prepared was injected into a mould formed bytwo glass sheets covered by spray mounted polyethyleneterephthalatesheet and separated using a polytetrafluoroethylene spacer.Polymerisation was carried out in situ by heating the mould to 80° C.for 2 hours.

The polymer sheet thus formed was removed from the mould and swollenwith water or a borate buttered saline solution at pH 7.1 to form ahydrogel sheet. The starting formulation is suitable for the mouldpolymerisation of soft contact lenses.

EXAMPLE 6 Formation of2(methacryloyloxyethyl)-2′(trimethylammonium)ethyl phosphate InnerSalt-co-2-hydroxyethyl-methacrylate-co-methylmethyacrylate-co-ethylenegycol-dimethacrylateMembrane

The method of Example 5 was repeated just using2(methacryloyloxyethyl)-2′(trimethylammonium)ethyl phosphate inner salt(compound C) (3.79 g), in 2-hydroxyethyl-methacrylate (8.39 g) togetherwith methylmethacrylate (5.04 g), ethyleneglycoldimethacrylate (0.254 g)as crosslinking agent and azobisisobutyronitrile (0.15 g) as apolymerisation initiator.

The resultant hydrogel sheet is similar to that obtained in Example 5.The starting formulation is suitable for the mould polymerisation ofsoft contact lenses.

EXAMPLE 7 Formation of 2-(trimethylammonium)ethyl methacrylatetrifluoromethane sulphate-co-2-hydroxyethylmethacrylate-co-methylenebis-acrylamide polymer Sheet

2-(trimethylammonium)ethyl methacrylate trifluoro-methanesulphonate,compound A, (0.25 g) was dissolved in hydroxyethyl methacrylate (5 g)together with methylene bis-acrylamide (25 mg) as cross-linking agentand benzoyl peroxide (25 mg) as polymerisation initiator. The resultingmonomer solution was then deoxygenated by bubbling nitrogen through for5 minutes.

The monomer solution thus prepared was injected into a mould formed bytwo silylated glass plates separated by a teflon spacer. Polymerisationwas carried out in situ by heating the mould to 70° C. and maintainingit at that temperature for 2 hours.

The polymer sheet formed was removed from the mould and swollen withwater or a saline solution to form a hydrogel sheet, which is a materialsuitable for forming into soft contact lenses.

EXAMPLE 8 Preparation of Further Copolymers

The method of Example 6 was repeated using, respectively, each ofcompounds B and C and compound types D to G prepared as described in theReference Examples in place of compound A. The hydrogel sheet formed ineach case was suitable for forming into soft contact lenses.

Mechanical Testing of Copolymers

The copolymer sheets and lenses produced may be swelled in appropriateaqueous solutions and then dehydrated by heating. The water content maybe determined by weight.

Tear strength measurement may be performed by Instrom analysis usingappropriate ASTM procedures. Oxygen permeability may be determined withappropriate electrodes in accordance with appropriate ASTM standards.The absorption of tear proteins by the copolymers may be measured bystandard spectrophotometic techniques.

EXAMPLE 9 Lathe Cutting to Produce Contact Lenses

Buttons (as prepared in Example 1) were mounted using a low meltingpoint wax and cut with a lathe speed of 2800 rpm to produce contactlenses. Cutting times were 1-2 seconds for 0.01 mm thickness reductionfrom the edge to the centre. Nitrogen may be used to cool the diamondbutton interface. The contact lenses produced were cleaned withpetroleum ether (60-80) and polished with an oil based polish (SP2).

EXAMPLE 10 Protein Adsorption and Equilibrium Water Content Study

Two hydrogel membranes of comparable water content were prepared:membrane A (comparative) comprised of methacrylic acid (16.5 mole %),2-hydroxyethylmethacrylate, (83.3 mole %) and ethyleneglycoldimethacrylate (0.2 mole %); membrane B according to the inventioncomprised of 2(methacryloyloxyethyl)-2′(trimethylammonium)ethylphosphate inner salt (40% mole), methylmethacrylate (59 mole %) andethylene glycol dimethacrylate (1%). Both membranes were cut into 0.9 mmdiscs and soaked in a buffered protein solution for 24 hours at 35° C.Control lenses were soaked in buffer solution for the same length oftime. The buffer solution was the same as that of the buffered proteinsolution except that the bovine albumin and chicken lysozyme were notadded.

The composition of the buffered protein solution was as follows:

Sodium Chloride 0.85% Boric Acid 0.46% Sodium Borate (10 H₂O) 0.04%Bovine Albumin 0.29% Chicken Egg Lysozyme 0.12% Water 98.4%

The conditions chosen mimic the occular environment and are equivalentto those experienced by a contact lens during 7 days wear. Theequilibrium water content was measured thermogravitmetrically and thedry weights of the membranes compared after soaking in the buffersolution and the buffered protein solution.

The equilibrium water content data and changes in dry weight equivalentto the adsorption of protein from the solution are shown below:

Increase in Dry Equilibrium Water Weight (g. Protein/g Membrane Content% Polymer A 79.4 ± 0.6 — at 35° C. A 75.9 ± 0.9 0.13 ± 0.04 at 35° C. inprotein solution B 70.5 ± 0.4 — At 35° C. B At 35° C. in 71.1 ± 0.5 0.01± 0.05 protein solution

The membrane containing2(methacryloyloxyethyl)-2′(trimethylammonium)ethyl phosphate inner saltwas found to absorb significantly less protein than a membrane materialof comparable water content. The equilibrium water content also remainedunchanged.

Reference Example 1 Synthesis of 2(trimethylammonium)ethylmethacrylatetrifluoromethanesulphonate (Compound A)

2(Dimethylamino)ethylmethacrylate was vacuum distilled and thendissolved in 0.1M dichloromethane. Methyltrifluoromethyl sulphonate (onemolar equivalent) was added slowly to the resulting solution, thetemperature of the solution being maintained throughout at 40° C. orless. The product precipitated out slowly and was recovered byfiltration and washed in cold dichloromethane. The synthesis is depictedin Reaction Scheme B.

Reference Example 2 Synthesis ofdimethyl(2-methacryloxyethyl)-(1(2-sulphopropyl)) ammonium betaine InnerSalt (Compound B)

2(Dimethylamino)ethylmethacrylate was vacuum distilled and thendissolved in 0.1M dichloromethane. To this solution was added anequimolar amount of propane sultone. The betaine slowly precipitated outof solution and was recovered by filtration and washed with colddichloromethane. The reaction is shown in Reaction Scheme B.

Reference Example 3 Preparation of2(methacryloyloxyethyl)-2′(trimethylammonium ethyl phosphate Inner Salt(Compound C)

The preparation is illustrated by the reaction scheme C which follows.

a) 2-Chloro-1,3-dioxaphospholane (1)

In a flask fitted with a pressure equalising dropping funnel, refluxcondenser (fitted with a CaCl₂ guard tube) and magnetic stirrer, wasplaced a solution of phosphorus trichloride (220 ml; 346.3 g; 2.52 mol)in dichloromethane (500 ml). Ethylene glycol (139 ml; 154.7 g, 2.49 mol)was then added dropwise via the dropping funnel at such a rate that theevolution of HCl did not become too excessive. On the addition of theethylene glycol, the condenser was arranged for distillation, and thedichloromethane removed at atmospheric pressure. When the distillatetemperature reached 60° C. the flask was arranged for vacuumdistillation using a water pump, Distillation then gave2-chloro-1,3-dioxaphospholane (158 ml; 224.5 g; 71.3%) as a colourlessmobile liquid (which fumes in moist air) b.pt. 36-40° C./21 mm Hg. [cf45.5-47° C./20 mm Hg, Lucas et al, J. Am. Chem. Soc., 72, 5491, (1950)].

IR (cm⁻¹, thin film) 2980, 2905, 1470, 1210, 1005, 930, 813, 770.

b) 2-Chloro-2-oxo-1,3,2-dioxaphospholane (2)

In a flask fitted with a magnetic stirrer, reflux condenser (fitted witha CaCl₂ guard tube) and sintered glass gas inlet tube, was placed asolution of 2-chloro-1,3-2-dioxaphospholane (100.8 g; 0.797 mol) in drybenzene (200 ml). The solution was stirred and a steady stream of oxygenwas bubbled through the solution. The reaction was mildly exothermic,and temperature control was achieved by allowing the solvent to reflux.The oxygen was passed through the reaction mixture for 6 hours. Thesolvent was removed by rotary evaporation, and the colourless mobileresidue distilled to give 2-chloro-2-oxo-1,3,2-dioxaphospholane (2)(87.41 g; 77%) as a colourless mobile liquid—b.pt 95-97° C./0.2 mbar[c.f. 102.5-105° C./1 mbar (Edmundson, Chem. Ind. (London)), 1828(1962); 79° C./0.4 mbar (Umeda et al., Makromaol. Chem. Rapid Communo.,3, 457, (1982)].

IR(cm⁻¹, thin film) 2990, 2910, 1475, 1370, 1310, 1220, 1030, 930, 865,830.

2(2-Oxo-1,3,2-dioxphospholan-2-yloxoy)ethyl methacrylate (3)

In a flask fitted with a magnetic stirrer, low temperature thermometer,and a pressure equalising funnel fitted with a silica gel guard tube,was placed a solution of 2-hydroxyethylmethacrylate (20.00 g, 0.154 mol)and triethylamine (15.60 g; 0.154 mol) in dry diethyl ether (300 ml).The solution was stirred and cooled to between −20° C. and −30° C. Asolution of freshly distilled 2-chloro-2-oxo-1,3,2-dioxaphospholane(2)(21.9 g; 0.154 mol) in dry diethyl ether (20 ml) was then added dropwiseover 30 minutes, the temperature being held at −20° C. during theaddition. Stirring was continued at this temperature for a further 1hour and then for a further hour as the reaction mixture was allowed towarm to room temperature. The precipitated triethylamine hydrochloridewas removed by filtration, and was washed well with dry ether. The etherwas removed from the combined filtrate and washings by rotaryevaporation. The cloudy oil residue was then shaken for 5 minutes withdry diethyl ether (50 ml) to precipitate a further crop of triethylaminehydrochloride, which was again removed by filtration. Removal of theether on the rotary evaporator gave (3) (34.18 g; 94.3%) as a colourlessviscous oil.

IR (cm⁻¹, thin film) 1720, 1640, 1450, 1360, 1310, 1290, 1170, 1030,930, 850.

NMR (CDCl₃; 60 MHz, δ ppm) 1.95 (s,3H), 4.25-4.70 (m,8H), 5.70 (m,1H),6.25 (m,1H).

Rf (SiO₂, eluting with 10% MeOH:90% CH₂Cl₂ −0.9; spot visualised withmolybdenum blue spray reagent (eg Sigma), and with iodine vapour).

d) 2(Methyacryloyloxyethyl)-2(trimethylammonium)ethyl phosphate InnerSalt (4)

The phospholane (3) (67.20 g; 0.285 mol was dissolved in 100 ml of dryacetonitrile, and placed in a heavy walled tissue culture bottle. Thephospholane solution was then treated with a solution of anhydroustrimethylamine (25.74 g; 0.436 mol) in dry acetonitrile (100 ml). Thevessel was then sealed, and placed in a water bath held at 50° C. for 30hours. The vessel was opened, and the solution brought to the boil. Thesolution was filtered whilst hot, and then set aside forcrystallisation.

The product was collected by filtration, and most of the solvent removedby suction. The wet product was then washed thoroughly with anhydrousether, then dried in vacuo, to give (4) as a white amorphous,hygroscopic solid (51.16 g; 61%). Evaporation of the mother liquor gavea very viscous oil (20.00 g; 23%), from which further product (4)crystallised on standing at −2° C. TLC (silica gel plates, eluting withMeOH/CH₂Cl₂ (1:1 v/v)) showed one spot Rf 0.1, which was revealed withDragendorffs reagent, Molybdenum blue spray reagent, and iodine vapour.

IR(cm⁻¹ 1720, 1640, 1320, 1300, 1230, 1170, 970, 750.

NMR (D₂O; 60 MHz; δ ppm) 2.0 (s,3H), 3.27 (s,9H) 3.60-4.50 (m, 8H),5.80, (m,1H) and 6.25 (m,1H).

CHN Found: C, 42.98%; H, 7.88%; N, 4.42%; P, 10.51%.

CHN Theory: C, 44.75%; H, 7.46%; N, 4.75%; P, 10.51%.

(d1) 2-(Methacryloyloxyethyl)-2′-(trimethylammonium)ethyl phosphateInner Salt [Alternative Preparation]

Into a glass pressure bottle (300 cm³), were placed2-(2-oxo-1,3,2-dioxaphospholan-2-yloxy)ethyl methacrylate (10.0 g, 42mmol) prepared in step (c) and dry acetonitrile (60 cm³). The pressurebottle was cooled in cold water and then trimethylamine (2.5 g, 42 mmol)was rapidly added to the cold solution. The pressure bottle was closedand then shaken in a thermostat maintained at 55° C. for 2 hours. It wasthen allowed to come to room temperature and to stand overnight, and wasshaken again at 55° C. for 13 hours. After the reaction it was cooleddown in water to 10° C. It was rapidly filtered with filter paper. Thefiltrate was evaporated under reduced pressure with a stream of nitrogenfor 2 hours to afford the product (12.3 g, 98%) as a colourless viscousliquid which crytallised on standing in a freezer. The product could bepurified by preparative liquid chromatography.

Reference Example 4 1-alkanoyl-2-methacroyl phosphatidyl choline and1-metharyloyl-2-alkanoyl phosphatidyl choline (Compound Types D and E)

Glycerophosphorylcholine (0.01 mole), obtained by base hydrolysis ofnatural phosphatidylcholine, may be stirred with alkynoic acid anhydride(0.01 mole) and dimethylamino pyridine (0.01 mole) in dimethylsulphoxide(150 cm³).

At the conclusion of this reaction further dimethylamino pyridine (1mole) together with methacrylic acid anhydride (1 mole) may be added.The resulting mixture may be stirred for 24 hours. Thephosphatidylcholine formed may be purified by column chromatography onsilica using a gradient elution procedure withchloroform:methanol:water.

The synthesis is depicted in reaction scheme D in which R=CH₃.

Reference Example 5 Synthesis of 1-alkanoyl-2-acroyl phosphatidylcholineand 1-acroyl-2-alkanoyl phosphatidylcholine (Compounds Type F and G)

The procedure of Reference Example 4 may be repeated, but with acrylicacid anhydride (1 mole) being used in place of methacrylic acidanhydride. The synthesis is depicted in Reaction Scheme D in which R=H.

Reference Example 6 Preparation of1[4(4′-vinylbenzyloxy)butane]-2″-(trimethylammonium)ethyl phospate InnerSalt

The synthesis is depicted in Reaction Scheme E.

4-Hydroxy-1(4′-vinylbenzyloxy)butane (5)

1,4-Butanediol (50.00 g) was dissolved in dry toluene (60 ml),para-choloromethylstyrene (15.62 g; 0.1 mol) was then added withstirring. A catalytic quantity of 18-crown-6 (0.3 g) was then added. Theflask was stoppered, stirred at room temperature for 18 hours and for afurther 4 hours at 45-60°. The resulting solution was then poured in towater (500 ml) and extracted with dichloromethane (3×75 ml). Thecombined extracts were dried (MgSO₄) and evaporated (20°/21 mm) to givea yellow oil, which was distilled to give a yellow oil (14.33 g;69.6%).b.pt. 152-157°/1 mbar.

NMR (60 MHz: CDCl₃) 1.55 (m, 4H); 3.50 (m, 5H, 1H exch); 4.45, (s, 2H)5.50 (dd, 2H), 6.75 (dd, 1H), 7.40 (m, 4H).

IR (thin film), 3402, 2938, 2888, 1631, 1602, 1582, 1511, 1480, 1445,1382, 1320, 1116, 1063, 920, 907, 827, 801, 716 and 667 cm⁻¹.

4(2-Oxo-1,3,2-dioxaphospholane-2-yloxy)-1(4′-vinylbenyloxy)butane (6)

4-Hydroxy-1(4′-vinylbenzyloxy)butane (5) (10.03 g; 48.69 mmol) and driedtriethylamine (4.92 g, 48.69 mmol) were dissolved in dry diethyl ether(150 ml) and the resulting solution placed in a rigorously dried flask.The solution was cooled to −30° and2-chloro-2-oxo-1,3,2-dioxaphospholane (6.94 g; 48.69 mmol) addeddropwise over 30 minutes, the temperature being held at −30°. Thereaction mixture was then stirred for a further 2 hours, during whichtime the temperature was allowed to rise to 100. The mixture wasfiltered and the precipitate washed with dry ether. The filtrate wasevaporated (20°/21 mm) to give a cloudy oil. The residue was shaken with50 ml of dry ether and refiltered. Evaporation of the filtrate gave theproduct as a viscous yellow oil (13.73 g; 90.4%).

TLC (eluting with 10% MeOH/90% dichloramethane) showed one major spot,which stained with acid molybdate reagent (Rf 0.61), IR (thin film)3458, 2945, 2917, 2860, 1630, 1602, 1581, 1475, 1419, 1363, 1283, 1103,1032, 820, 842, 807, 800, 715, 610 and 421 cm⁻¹.

1[4(4′-Vinylbenzyloxy)butane]-2″(trimethylammonium)ethyl phosphate InnerSalt (7)

Trimethylamine (2.00 g, 33.9 mmol) was distilled into a reaction vessel,and frozen with liquid nitrogen. A solution of the4(2-oxo-1,3,2-dioxaphospholane-2-yloxy)-1-(4′-vinylbenyloxy)butane (6)(10.00 g, 32.1 mmol) in anhydrous acetonitrile (40 ml) was then added tothe reaction vessel, which was then sealed and placed in a thermostattedwater bath (50° for 50 hours). The reaction vessel was then cooled toroom temperature, opened, and the reaction mixture evaporated to abouthalf its original volume (21 mm pressure). The concentrated solution wasthen stirred at room temperature, whilst anhydrous ether (200 ml) wasadded dropwise to precipitate the product as a viscous oil. The mixturewas then left for several hours at −10°. The product was collected bydecanting off the supernatent solid. TLC (eluting withmethanol/dichloromethane 1:1) showed one major spot at Rf 0.0-0.1 whichstained with both Dragendorffs reagent and acid molybdate.

What is claimed is:
 1. A cross-linked polymer obtained by polymerizing amixture consisting essentially of: i) a zwitterionic monomer of theformula (V):

wherein BB is a straight or branched C₁-C₆ alkylene chain optionallyinterrupted by one or more oxygen atoms: nn is from 1 to 12; R¹¹ is H ora C₁-C₄ alkyl group; and YY is a zwitterionic group which is selectedfrom the group consisting of:

wherein mm is 1 to 4, nn is 1 to 12 and BB is a straight or branchedC₁-C₆ alkylene chain optionally interrupted by one or more oxygen atoms;ii) a non-ionic diluent monomer; and iii) a cross-linking monomer whichforms cross-links during the polymerization reaction.
 2. A cross-linkedpolymer according to claim 1, in which the diluent monomer is selectedfrom the group consisting of alkyl (alk)acrylates, dialkylamino alkyl(alk)acrylates, alkyl (alk)acrylamides, hydroxyalkyl (alk)acrylates,N-vinyl lactams, styrene, substituted styrene, and mixtures thereof. 3.A cross-linked polymer according to claim 2, in which the diluentmonomer is selected from the group consisting of vinylpyrrolidone,2-hydroxyethylmethacrylate, methylmethacrylate and mixtures thereof. 4.A cross-linked polymer according to claim 3 wherein the diluent monomeris 2-hydroxyethylmethacrylate.
 5. A cross-linked polymer according toclaim 3, wherein the diluent monomer is methylmethacrylate.
 6. Across-linked polymer according to claim 1, in which the cross-linkingmonomer is a bifunctional or trifunctional cross-linking agent.
 7. Across-linked polymer according to claim 6, in which the cross-linkingmonomer is selected from the group consisting ofethyleneglycoldimethacrylate, trimethylolpropane trimethacrylate andN,N′-methylenebisacrylamide.
 8. A cross-linked copolymer according toclaim 1, in which YY is a group of formula (VIC).
 9. A cross-linkedpolymer according to claim 1, in which YY is a group of formula (VID).10. A cross-linked polymer according to claim 1, in which the group YYis a group of formula (VIE).
 11. A cross-linked polymer according toclaim 1, wherein the group R¹¹ is hydrogen or methyl.
 12. A cross-linkedpolymer according to claim 1, in which the zwitterionic monomer of theformula V is 2(methacryloyloxy)ethyl-2′-(trimethylammonium)ethylphosphate inner salt.
 13. A cross-linked polymer according to claim 12,in which the diluent monomer is 2-hydroxyethylmethacrylate.
 14. Ahydrogel comprising a cross-linked polymer according to claim 1, andwater in an amount of from 30 to 80% by weight of the hydrogel.
 15. Axerogel comprising a cross-linked polymer according to claim 1, which isfree of water.
 16. A cross-linked polymer obtained by polymerizing amixture consisting essentially of; i) a zwitterionic monomer of formula(I): Y—B—X  (I) wherein B is a straight or branched alkylene,oxaalkylene or oligo-oxaalkylene chain or if X contains a carbon-carbonchain between B and the zwitterionic group or if K is joined to B via acarbon atom, a valence bond, Y is an ethylenically unsaturatedpolymerizable group selected from:

wherein: R is hydrogen or a C₁-C₄ alkyl group; A is —O— or —NR¹— whereR¹ is hydrogen or a C₁-C₄ alkyl group or R¹ is —B—X where B and X are asdefined above; and K is a group —(CH₂)_(p)OC(O)—, —(CH₂)_(p)C(O)O—,—(CH₂)_(p)OC(O)O—, —(CH₂)_(p)NR²—, —(CH₂)_(p)NR²C(O)—,—(CH₂)_(p)C(O)NR²—, —(CH₂)_(p)NR²C(O)O—, —(CH₂)_(p)NR²C(O)O—,—(CH₂)_(p)OC(O)NR²—, —(CH₂)_(p)NR²C(O)NR²— (in which the groups R² arethe same or different), —(CH₂)_(p)O—, —(CH₂)_(p)SO₃—, or, optionally ina combination with B, a valence bond, and p is from 1 to 12 and R² ishydrogen or a C₁-C₄ alkyl group and X is selected from the groupconsisting of groups of formula (IVC):

wherein the groups R⁷ are the same or different and each is hydrogen orC₁₋₄ alkyl, and e is 1, 3 or 4; groups of formula (IVD):

wherein the groups R⁸ are the same or different and each is hydrogen orC₁₋₄ alkyl, B¹ is a valence bond or straight or branched alkylene,oxaalkylene or oligo-oxaalkylene group, f is from 1 to 4 and if B isother than a valence bond, z is 1 and if B is a valence bond z is 0 if Xis directly bonded to an oxygen or nitrogen atom and otherwise z is 1;groups of formula (IVE):

wherein the groups R⁹ are the same or different and each is hydrogen orC₁₋₄ alkyl, B² is a valence bond or a straight or branched alkylene,oxaalkylene or oligo-oxaalkylene group, g is from 1 to 4 and if B isother than a valence bond, z is 1 and if B is a valence bond z is 0 if Xis directly bonded to an oxygen or nitrogen atom and otherwise z is 1;and groups of formula (IVF):

wherein the groups R¹⁰ are the same or different and each is hydrogen orC₁₋₄ alkyl, B³ is a valence bond or a straight or branched alkylene,oxaalkylene or oligo-oxaalkylene group, h is from 1 to 4 if B is otherthan a valence bond, z is 1 and if B is a valence bond z is 0 if X isdirectly bonded to an oxygen or nitrogen atom and otherwise z is 1; ii)a non-ionic diluent monomer; and iii) a cross-linking monomer whichforms cross-links during the polymerization reaction.
 17. A cross-linkedpolymer according to claim 16, in which the diluent monomer is selectedfrom the group consisting of alkyl (alk)acrylates, dialkylamino alkyl(alk)acrylates, alkyl (alk)acrylamides hydroxyalkyl (alk)acrylates,N-vinyl lactams, styrene, substituted styrene; and mixtures thereof. 18.A cross-linked polymer according to claim 17, in which the diluentmonomer is selected from the group consisting of vinylpyrrolidone,2-hydroxyethylmethacrylate, methylmethacrylate and mixtures thereof. 19.A cross-linked polymer according to claim 16, in which B is an alkylenegroup of formula —(CR³ ₂)_(a)—, wherein the groups —(CR³ ₂)— are thesame or different, and in each group —(CR³ ₂)— the groups R³ are thesame or different and each group R³ is hydrogen or C₁-C₄ alkyl, and a isfrom 1 to 12; an alkoxyalkyl group having 1 to 6 carbon atoms in eachalkyl moiety; an oligo-oxaalkylene group of formula —[(CR⁴₂)_(b)O]_(c)(CR⁴ ₂)_(b)— where the groups —(CR⁴ ₂)— are the same ordifferent and in each group —(CR⁴ ₂)— the groups R⁴ are the same ordifferent and each group R⁴ is hydrogen or C₁-C₄ alkyl, and b is 2 or 3and c is from 2 to 11, or if X contains a carbon-carbon chain between Band the center of positive charge, or if K is joined to B via a carbonatom, a valence bond.
 20. A cross-linked polymer according to claim 16,in which X is a group of formula (IVD), (IVE) or (IVF) and B¹, B² orB³¹, respectively, contains up to 24 carbon atoms.
 21. A cross-linkedpolymer according to claim 16, in which the group X is a group offormula (IVC).
 22. A cross-linked polymer according to claim 21, whereinthe groups R⁷ are all methyl.
 23. A cross-linked polymer according toclaim 16, in which cross-linking monomer is a bifunctional ortrifunctional cross-linking agent.
 24. A cross-linked polymer accordingto claim 23, in which the cross-linking agent is selected from the groupconsisting of ethyleneglycoldimethacrylate,trimethylolpropanetrimethacrylate and N,N′-methylenebisacrylamide.
 25. Ahydrogel comprising a cross-linked polymer according to claim 16, andwater in an amount of from 30 to 80% by weight of the hydrogel.
 26. Axerogel comprising a cross-linked polymer according to claim 16 which isfree of water.
 27. A process for producing a cross-linked copolymer bycopolymerizing a monomer solution consisting essentially of a non-ionicdiluent monomer or monomers, a zwitterionic monomer or monomers and across-linking monomer, wherein said zwitterionic monomer or monomers hasthe formula (V):

wherein BB is a straight or branched C₁-C₆ alkylene chain optionallyinterrupted by one or more oxygen atoms: nn is from 1 to 12; R¹¹ is H ora C₁-C₄ alkyl group; and YY is a zwitterionic group which is selectedfrom the group consisting of:

wherein mm is 1 to 4, nn is 1 to 12 and BB is a straight or branchedC₁-C₆ alkylene chain optionally interrupted by one or more oxygen atoms.28. A process for producing a cross-linked copolymer by copolymerizing amonomer solution consisting essentially of a non-ionic diluent monomeror monomers, a zwitterionic monomer or monomers and a cross-linkingmonomer, wherein said zwitterionic monomer or monomers has the formula(I) Y—B—X  (I) wherein B is a straight or branched alkylene, oxaalkyleneor oligo-oxaalkylene chain or if X contains a carbon-carbon chainbetween B and the zwitterionic group or if K is joined to B via a carbonatom, a valence bond; Y is an ethylenically unsaturated polymerizablegroup selected from:

wherein: R is hydrogen or a C₁-C₄ alkyl group; A is —O— or —NR¹— whereinR¹ is hydrogen or a C₁-C₄ alkyl group or R¹ is —B—X where B and X are asdefined above; and K is a group —(CH₂)_(p)OC(O)—, —(CH₂)_(p)C(O)O—,—(CH₂)_(p)OC(O)O—, —(CH₂)_(p)NR²—, —(CH₂)_(p)NR²C(O)—, —(CH₂_(p)C(O)NR²—, —(CH₂)_(p)NR²C(O)O—, —(CH₂)_(p)NR²C(O)O—,—(CH₂)_(p)OC(O)NR²—, —(CH₂)_(p)NR²C(O)NR²— (in which the groups R² arethe same or different), —(CH₂)_(p)O—, —(CH₂)_(p)SO₃—, or, optionally ina combination with B, a valence bond, and p is from 1 to 12 and R² ishydrogen or a C₁-C₄ alkyl group and X is selected from the groupconsisting of groups of formula (IVC):

wherein the groups R⁷ are the same or different and each is hydrogen orC₁₋₄ alkyl, and e is 1, 3 or 4: groups of formula (IVD):

wherein the groups R⁸ are the same or different and each is hydrogen orC₁₋₄ alkyl, B¹ is a valence bond or straight or branched alkylene,oxaalkylene or oligo-oxaalkylene group, f is from 1 to 4 and if B isother than a valence bond, z is 1 and if B is a valence bond z is 0 if Xis directly bonded to an oxygen or nitrogen atom and otherwise z is 1;groups of formula (IVE):

wherein the groups R⁹ are the same or different and each is hydrogen orC₁₋₄ alkyl, B² is a valence bond or a straight or branched alkylene,oxaalkylene or oligo-oxaalkylene group, g is from 1 to 4 and if B isother than valence bond, z is 1 and if B is a valence bond z is 0 if Xis directly bonded to an oxygen or nitrogen atom and otherwise z is 1;and groups of formula (IVF):

wherein the groups R¹⁰ are the same or different and each is hydrogen orC₁₋₄ alkyl, B³ is a valence bond or a straight or branched alkylene,oxaalkylene or oligo-oxaalkylene group, h is from 1 to 4 if B is otherthan a valence bond, z is 1 and if B is a valence bond z is 0 if X isdirectly bonded to an oxygen or nitrogen atom and otherwise z is
 1. 29.A process according to claim 27, in which the zwitterionic monomer ormonomers and diluent monomer or monomers are immiscible and in which thereaction mixture for the polymerization includes a solvent in which allthe monomers are dissolved.
 30. A process according to claim 27, inwhich the diluent monomer or monomers comprises alkyl(alk)acrylatehaving 1-12 carbon atoms in the alkyl group.
 31. A process according toclaim 30, in which the diluent monomer is methylmethacrylate.
 32. Aprocess according to claim 31, in which the solvent is selected fromethanol, methanol and water.
 33. A process according to claim 27 inwhich the reaction mixture is free of water such that the polymerizationproduces a xerogel and in which the xerogel is hydrated with water toproduce a hydrogel containing from 30 to 80% water.
 34. A processaccording to claim 32, in which the solvent is present in an amount inthe range of 5-40 wt % based on the total reaction mixture.
 35. Aprocess according to claim 27, in which the comonomers are miscible. 36.A process according to claim 35, in which the polymerization mixture issubstantially free of solvent and of non-polymerizable diluent.
 37. Aprocess according to claim 36 in which after polymerization thecross-linked polymer is hydrated to form a hydrogel containing from 30to 80% by weight water.
 38. A process according to claim 35, in whichthe diluent monomer comprises hydroxy alkyl(alk)acrylate in which thehydroxy alkyl group contains in the range of from 1-4 carbon atoms. 39.A process according to claim 38, in which the diluent monomer is2-hydroxyethylmethacrylate.
 40. A process according to claim 27, inwhich the cross-linking agent is a bifunctional or trifunctionalmonomer.
 41. A process according to claim 40, in which the cross-linkingagent is selected from the group consisting ofethyleneglycoldimethacrylate, trimethylolpropanetrimethacrylate andN,N′-methylene bisacrylamide.
 42. A process according to claim 27, inwhich the cross-linking agent is present in an amount of 0.10 to 10% byweight based upon total monomer weight.
 43. A process according to claim27, in which YY is a group of formula (VIC).
 44. A process according toclaim 27, in which YY is a group of formula (VID).
 45. A processaccording to claim 27, in which the group YY is a group of formula(VIE).
 46. A process according to claim 27, wherein the group R¹¹ ishydrogen or methyl.
 47. A process according to claim 27, in which thezwitterionic monomer of the formula V is2-(methacryloyloxyethyl)-2′-(trimethylammonium)ethyl phosphate innersalt.
 48. A process according to claim 27, in which the diluent monomeris 2-hydroxyethyl methacrylate.
 49. A process according to claim 28, inwhich the zwitterionic monomer or monomers and diluent monomer ormonomers are immiscible and in which the reaction mixture for thepolymerization includes a solvent in which all the monomers aredissolved.
 50. A process according to claim 49, in which the diluentmonomer or monomers comprises alkyl(alk)acrylate having 1-12 carbonatoms in the alkyl group.
 51. A process according to claim 50, in whichthe diluent monomer is methylmethacrylate.
 52. A process according toclaim 49, in which the solvent is selected from ethanol, methanol andwater.
 53. A process according to claim 49, in which the reactionmixture is free of water such that the polymerization produces a xerogeland in which the xerogel is hydrated to from a hydrogel containing from30 to 80% of water.
 54. A process according to claim 28, in which thesolvent is present in an amount in the range of 5-40 wt % based on thetotal reaction mixture.
 55. A process according to claim 28, in whichthe comonomers are miscible.
 56. A process according to claim 55, inwhich the polymerization mixture is substantially free of solvent and ofnon-polymerization diluent.
 57. A process according to claim 55, inwhich after polymerization the cross-linked polymer is hydrated to forma hydrogel containing from 30 to 80% by weight water.
 58. A processaccording to claim 55, in which the diluent monomer comprises hydroxyalkyl(alk)acrylate in which the hydroxy alkyl group contains in therange of from 1-4 carbon atoms.
 59. A process according to claim 58, inwhich the diluent monomer is 2-hydroxyethylmethacrylate.
 60. A processaccording to claim 28, in which the cross-linking agent is abifunctional or trifunctional monomer.
 61. A process according to claim60, in which the cross-linking agent is selected from the groupconsisting of ethyleneglycoldimethacrylate,trimethylolpropanetrimethacrylate, and N,N′-methylene bisacrylamide. 62.A process according to claim 28, in which the cross-linking agent ispresent in an amount in the range 0.1 to 10% by weight based upon totalmonomer weight.
 63. A process according to claim 28, in which X is agroup of formula (IVC).
 64. A process according to claim 28, in which Xis a group of formula (IVD).
 65. A process according to claim 28, inwhich the group X is a group of formula (IVE).
 66. A process accordingto claim 28, wherein the group R¹¹ is hydrogen or methyl.
 67. A contactlens material comprising a cross-linked polymer obtained by polymerizinga mixture consisting essentially of: i) a zwitterionic monomer of theformula (V):

wherein BB is a straight or branched C₁-C₆ alkylene chain optionallyinterrupted by one or more oxygen atoms: nn is from 1 to 12; R¹¹ is H ora C₁-C₄ alkyl group; and YY is a zwitterionic group VIB

ii) a non-ionic diluent monomer; and iii) a cross-linking monomer whichforms cross-links during the polymerization reaction selected from thegroup consisting of alkane diol di(alk)acrylates, alkane trioltri(alk)acrylates, alkylene di(alk)acrylamides, alkylenetri(alk)acrylamides, divinylbenzene, and trivinylbenzene.
 68. A contactlens material comprising a cross-linked polymer obtained by polymerizinga mixture consisting essentially of: i) a zwitterionic monomer offormula (I): Y—B—X  (I) wherein B is a straight or branched alkylene,oxaalkylene or oligooxaalkylene chain or if X contains a carbon-carbonchain between B and the zwitterionic group or it Y contains a terminalcarbon atom, a valence bond, Y is an ethylenically unsaturatedpolymerizable group selected from:

wherein: R is hydrogen or a C₁-C₄ alkyl group; A is —O— or —NR¹— whereR¹ is hydrogen or a C₁-C₄ alkyl group or R¹ is —B—X where B and X aredefined above; and K is a group —(CH₂)_(p)OC(O)—, —(CH₂)_(p)C(O)O—,—(CH₂)_(F)OC(O)O—, —(CH₂)_(p)NR²—, —(CH₂)_(p)NR²C(O)—,—(CH₂)_(p)C(O)NR²—, —(CH₂)_(p)NR²C(O)O—, —(CH₂)_(p)NR²C(O)O—,—(CH₂)_(p)OC(O)NR²—, —(CH₂)_(p)NR²C(O)NR²—, (in which the groups R² arethe same or different), —(CH₂)_(p)O—, —(CH₂)_(p)SO₃—, or, optionally ina combination with B, a valence bond, and p is from 1 to 12 and R² ishydrogen or a C₁-C₄ alkyl group and X is IVB

wherein the groups R⁶ are the same or different and each is hydrogen orC₁₀₄ alkyl and d is from 2 to 4, II ii) a non-ionic diluent monomer; andiii) a cross-linking monomer which forms cross-links during thepolymerization reaction selected from the group consisting of alkanediol di(alk)acrylates, alkane triol tri(alk)acrylates, alkylenedi(alk)acrylamides, alkylene tri(alk)acrylamides, divinylbenzene, andtrivinylbenzene.
 69. A contact lens which is a hydrogel formed from acontact lens material according to claim 67 or 68 and water in an amountfrom 30 to 80% by weight.
 70. A cross-linked polymer according to claim1 obtained by polymerizing at least 0.2% by weight of said zwitterionicmonomer at least 70% by weight of said diluent monomer, and at least0.01% by weight of said cross-linking monomer, said weight proportionsbeing based on the total weight of monomer.
 71. A cross-linked polymeraccording to claim 16, obtained by polymerizing at least 0.2% by weightof said zwitterionic monomer at least 70% by weight of said diluentmonomer, and at least 0.01% by weight of said cross-linking monomer,said weight proportions being based on the total weight of monomer. 72.A process according to claim 27, wherein said copolymerization comprisescopolymerizing at least 70% by weight of said non-ionic diluent monomeror monomers, at least 0.2% by weight of said zwitterionic monomer ormonomers and at least 0.01% by weight of said cross-linking agent, saidweight proportions being based on the total weight of monomers.
 73. Aprocess according to claim 28, wherein said copolymerization comprisescopolymerizing at least 70% by weight of said non-ionic diluent monomeror monomers, at least 0.2% by weight of said zwitterionic monomer ormonomers and at least 0.01% by weight of said cross-linking agent, saidweight proportions being based on the total weight of monomers.
 74. Acrosslinked polymer obtained by polymerizing a mixture consistingessentially of: i) a zwitterionic monomer of formula (I): Y—B—X  (I)wherein B is a straight or branched alkylene, oxaalkylene oroligo-oxaalkylene chain, Y is a group of formula CH₂═C(R)—C(O)—A—wherein: R is hydrogen or a C₁-C₄ alkyl group; A is —O— or —NR¹— whereR¹ is hydrogen or a C₁₋₄-alkyl group or R¹ is —B—X where B is definedabove and X is as defined below; and X is selected from the groupconsisting of groups of formula (IVC):

wherein the groups R⁷ are the same or different and each is hydrogen orC₁₋₄ alkyl, and e is 1, 3 or 4; groups of formula (IVD):

wherein the groups R⁸ are the same or different and each is hydrogen orC₁₋₄ alkyl, B¹ is a valence bond or straight or branched alkylene,oxaalkylene or oligo-oxaalkylene group, f is from 1 to 4 and z is 1;groups of formula (IVE):

wherein the groups R⁹ are the same or different and each is hydrogen orC₁₋₄ alkyl, B² is a valence bond or a straight or branched alkylene,oxaalkylene or oligo-oxaalkylene group, g is from 1 to 4 and z is 1; andgroups of formula (IVF):

wherein the groups R¹⁰ are the same or different and each is hydrogen orC₁₋₄ alkyl, B³ is a valence bond or a straight or branched alkylene,oxaalkylene or oligo-oxaalkylene group, h is from 1 to 4 and z is 1; ii)a non-ionic diluent monomer; and iii) a cross-linking monomer whichforms cross-links during the polymerization reaction.
 75. A process forproducing a crosslinked copolymer by copolymerizing a solutioncontaining mixture of monomers consisting essentially of a non-ionicdiluent monomer or monomers, a zwitterionic monomer or monomers and acrosslinking monomer, wherein said zwitterionic monomer or monomers hasthe formula (I): Y—B—X  (I) wherein B is a straight or branchedalkylene, oxaalkylene or oligo-oxaalkylene chain, Y is a group offormula CH₂═C(R)—C(O)—A— wherein: R is hydrogen or a C₁-C₄ alkyl group;A is —O— or —NR¹— where R¹ is hydrogen or a C₁₋₄-alkyl group or R¹ is—B—X where B is defined above and X is as defined below; and X isselected from the group consisting of groups of formula (IVC):

wherein the groups R⁷ are the same or different and each is hydrogen orC₁₋₄ alkyl, and e is 1, 3 or 4; groups of formula (IVD):

wherein the groups R⁸ are the same or different and each is hydrogen orC₁₋₄ alkyl, B¹ is a valence bond or straight or branched alkylene,oxaalkylene or oligo-oxaalkylene group, f is from 1 to 4 and z is 1;groups of formula (IVE):

wherein the groups R⁹ are the same or different and each is hydrogen orC₁₋₄ alkyl, B² is a valence bond or a straight or branched alkylene,oxaalkylene or oligo-oxaalkylene group, g is from 1 to 4 and z is 1; andgroups of formula (IVF):

wherein the groups R¹⁰ are the same or different and each is hydrogen orC₁₋₄ alkyl, B³ is a valence bond or a straight or branched alkylene,oxaalkylene or oligo-oxaalkylene group, h is from 1 to 4 and z is 1; ii)a non-ionic diluent monomer; and iii) a cross-linking monomer whichforms cross-links during the polymerization reaction.
 76. A contact lensmaterial according to claim 67 in which the nonionic diluent monomer isselected from the group consisting of alkyl(alk)acrylates containing 1to 12 carbon atoms in the alkyl group; hydroxy alkyl(alk)acrylatecontaining from 1 to 4 carbon atoms in the hydroxy alkyl group, N-vinyllactam containing from 5 to 7 atoms in the lactam ring, styrene andalkyl(alk)acrylamides containing 1 to 4 carbon atoms in the alkyl group.77. A contact lens material according to claim 68 in which the nonionicdiluent monomer is selected from the group consisting ofalkyl(alk)acrylates containing 1 to 12 carbon atoms in the alkyl group;hydroxy alkyl(alk)acrylate containing from 1 to 4 carbon atoms in thehydroxy alkyl group, N-vinyl lactam containing from 5 to 7 atoms in thelactam ring, styrene and alkyl(alk)acrylamides containing 1 to 4 carbonatoms in the alkyl group.